Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that involves the lungs in over 90% of affected individuals and may cause end-stage pulmonary fibrosis and death. The pathologic hallmark of sarcoidosis is non-caseating granulomatous inflammation. A major step in understanding sarcoidosis would be the identification of infectious agents that trigger sarcoidosis. Recently, using a limited proteomic approach with matrix-associated laser desorption/ionization-time of flight mass spectrometry, we identified Mycobacterium tuberculosis catalase-peroxidase (mKatG) as a tissue antigen and target of the immune response in sarcoidosis, supporting a mycobacterial etiology of sarcoidosis. Our preliminary studies have shown that many sarcoidosis patients with active untreated disease have antigen-specific T cell and/or B cell responses to mKatG proteins. The goal of this application is to test the hypothesis that mKatG is a dominant pathogenic antigen in sarcoidosis as part of an adaptive immune response driving granulomatous inflammation in many, if not most, patients with sarcoidosis. We plan to test this hypothesis by identifying mKatG DNA in sarcoidosis tissues, by evaluating the T cell and B cell responses to mKatG proteins in patients with acute remitting and non-acute chronic sarcoidosis from both the US and Sweden, and by testing mKatG as a pathogenic antigen in experimental models of granulomatous inflammation. In Sweden, we will specifically evaluate Lofgren-prone DR17 positive sarcoidosis patients with good prognoses and DR17 negative patients who tend to have chronic disease for their T and B cell responses to mKatG proteins. These studies have the potential to establish one specific mycobacterial protein, mKatG, as a dominant pathogenic antigen in sarcoidosis that triggers and/or sustains the inflammation causing this disease. With this new information and an improved understanding of sarcoidosis, novel strategies aimed at curing or even preventing sarcoidosis may be devised. (End of Abstract)